Current Urology Reports

, Volume 13, Issue 2, pp 170–178

Therapeutic Options for Advanced Prostate Cancer: 2011 Update

Prostate Cancer (R Reiter, Section Editor)


Up to 40% of male patients diagnosed with prostate cancer develop metastatic disease that generally responds to initial chemical or surgical castration, but this eventually progresses despite castrate levels of testosterone, termed castration-resistant prostate cancer (CRPC). A large phase 3 trial of abiraterone acetate in patients who have progressed following docetaxel based chemotherapy were published in 2011 and dramatically proved that CRPC is still androgen-dependant and responds to CYP17 inhibition. Overall survival benefits were also reported for a novel tubulin-binding drug, cabazitaxel, tested as second-line chemotherapy after docetaxel failure; for sipuleucel-T, an autologous dendritic cell therapy, in chemotherapy-naive patients; for MDV3100, a novel antiandrogen, and for radium-223, which is a bone-seeking α-irradiation–emitting radioisotope. Denosumab, a monoclonal antibody against receptor activator of nuclear factor-kB ligand, was shown to be superior to zoledronic acid for prevention of skeletal-related events in prostate cancer patients with metastatic bone disease. This review will focus on the recent developments in the field of CRPC.


Prostate cancer Castrate-resistant prostate cancer CRPC Docetaxel Cabazitaxel Abiraterone Radium-223 Sipuleucel-T Denosumab Circulating tumor cells CTC Biomarker Update 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009;16(6):458–62.PubMedCrossRefGoogle Scholar
  2. 2.
    • Scher HI, Jia X, de Bono JS, et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10(3):233–9. CTCs are described as a predictive biomarker of overall survival in CRPC patients starting first-line systemic therapy in the IMMC38 trial.PubMedCrossRefGoogle Scholar
  3. 3.
    Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol. 2008;295(1–2):115–20.PubMedCrossRefGoogle Scholar
  4. 4.
    Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Barrie SE, Potter GA, Goddard PM, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50(5–6):267–73.PubMedCrossRefGoogle Scholar
  6. 6.
    Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28):4563–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28(9):1481–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28(9):1489–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496–501.PubMedCrossRefGoogle Scholar
  10. 10.
    •• de Bono JS, Logothetis CJ, Molina A, COU-AA-301 Investigators, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005. This phase 3 trial of abiraterone plus prednisone in docetaxel pretreated patients showed a survival benefit.PubMedCrossRefGoogle Scholar
  11. 11.
    • Fizazi K, Scher HI, Molina, et al. Final overall survival (OS) analysis of COU-AA-301, a phase 3 study of Abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) pretreated with docetaxel. Presented at the European Multidisciplinary Cancer Congress ECCO. Stockholm, Sweden 23–27 September 2011. EJC Volume 47 Supplement 2, September 2011, LBA1. The authors describe updated survival analysis for a phase 3 trial of abiraterone plus prednisone in docetaxel-pretreated patients. Google Scholar
  12. 12.
    Harland J, de Bono JS, Haqq CM, et al. Abiraterone acetate improves functional status in patients with metastatic castration resistant prostate cancer (mCRPC) post-docetaxel – results from the COU-AA-301 phase 3 study. Presented at the European Multidisciplinary Cancer Congress ECCO. Stockholm, Sweden 23–27 September 2011. EJC Volume 47 Supplement 2, September 2011, LBA1.Google Scholar
  13. 13.
    •• de Bono JS, Oudard S, Ozguroglu M, TROPIC Investigators, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147–54. This phase 3 trial of cabazitaxel plus prednisone showed survival benefit as second-line chemotherapy in CRPC.PubMedCrossRefGoogle Scholar
  14. 14.
    Pal SK, Twardowski P, Sartor O. Critical appraisal of cabazitaxel in the management of advanced prostate cancer. Clin Interv Aging. 2010;5:395–402. Review.PubMedCrossRefGoogle Scholar
  15. 15.
    Tannock IF, de Wit R, Berry WR, TAX 327 Investigators, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15(2):723–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Pivot X, Koralewski P, Hidalgo JL, et al. A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol. 2008;19(9):1547–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Ansari J, Hussain SA, Zarkar A, et al. Docetaxel chemotherapy for metastatic hormone refractory prostate cancer as first-line palliative chemotherapy and subsequent re-treatment: Birmingham experience. Oncol Rep. 2008;20(4):891–6.PubMedGoogle Scholar
  19. 19.
    Ross RW, Beer TM, Jacobus S, et al. Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer. 2008;112(3):521–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Di Lorenzo G, Figg WD, Fossa SD, et al. Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol. 2008;54(5):1089–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Di Lorenzo G, Buonerba C, Faiella A, et al. Phase II study of docetaxel re-treatment in docetaxel-pretreated castration-resistant prostate cancer. BJU Int. 2011;107(2):234–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Nilsson S, Larsen RH, Fosså SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12):4451–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Serafini AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4):1574–81.PubMedGoogle Scholar
  24. 24.
    Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer. 1991;27(8):954–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Ritter MA, Cleaver JE, Tobias CA. High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature. 1977;266(5603):653–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587–94.PubMedCrossRefGoogle Scholar
  27. 27.
    •• Parker C, Heidreich D, O’Sullivan, et al. Overall Survival Benefit of Radium-223 chloride (AlpharadinTM) in the treatment of patients with symptomatic bone metastases in castration resistant prostate cancer (CRPC): a phase III randomised trial ALSYMPCA. Presented at the European Multidisciplinary Cancer Congress ECCO. Stockholm, Sweden 23–27 September 2011. EJC Volume 47 Supplement 2, September 2011, LBA1. This is the first presentation of phase 3 data of radium-223 in CRPC showing overall survival benefit. Google Scholar
  28. 28.
    •• Kantoff PW, Higano CS, Shore ND, IMPACT Study Investigators, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. This is a phase 3 trial showing overall survival benefit of autologous dendritic cell vaccine in patients with CRPC.PubMedCrossRefGoogle Scholar
  29. 29.
    Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115(16):3670–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099–105.PubMedCrossRefGoogle Scholar
  32. 32.
    Scher HI, Jia X, Chi K, et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011;29(16):2191–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Chan JS, Ryan CW, Venner PM, Beer TM, et al. Skeletal related events (SREs) in metastatic androgen independent prostate cancer (AIPC) treated with docetaxel-based chemotherapy: Results from ASCENT. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 4614Google Scholar
  34. 34.
    Saad F, Gleason DM, Murray R, Zoledronic Acid Prostate Cancer Study Group, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879–82.PubMedCrossRefGoogle Scholar
  35. 35.
    • Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22. This is a phase 3 trial with direct comparison of denosumab versus zoledronic acid in CRPC patients.PubMedCrossRefGoogle Scholar
  36. 36.
    Attard G, de Bono JS. Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients. Clin Cancer Res. 2011;17(12):3867–75.PubMedCrossRefGoogle Scholar
  37. 37.
    •• de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–9. The authors describe that CTCs predict overall survival in CRPC.CrossRefGoogle Scholar
  38. 38.
    • Scher HI, Heller G, Molina A, et al. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J Clin Oncol. 2011;29 (suppl; abstr LBA4517^). This article describes the first results of CTC data of phase 3 abiraterone plus prednisone trial showing surrogacy of overall survival. Google Scholar
  39. 39.
    •• Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8. This article describes the molecular characterization of ERG, AR, and PTEN in CTC, important biomarkers that may be used for patient selection or stratification.PubMedCrossRefGoogle Scholar
  40. 40.
    • Scher HI, Beer TM, Higano CS, Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 2010;375(9724):1437–46. This is a phase 1/2 trial of MDV3100 in CRPC.PubMedCrossRefGoogle Scholar
  41. 41.
    Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, De Wit R, Mulders P, Hirmand M, Selby B, De Bono JS, Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. J Clin Oncol. 2012;30 (suppl 5; abstr LBA1).Google Scholar
  42. 42.
    Dreicer R, Agus DB, MacVicar GR G, et al. Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study. J Clin Oncol. 2010;28:15s. suppl; abstr 3084.Google Scholar
  43. 43.
    Gordon MS, Vogelzang NJ, P. Schoffski P, et al. Activity of cabozantinib (XL184) in soft tissue and bone: results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors. J Clin Oncol. 2011;29 (suppl; abstr 3010).Google Scholar
  44. 44.
    •• Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575–86. This article describes preclinical data of cross-talk and reciprocal regulation of AR and PI3K pathways.PubMedCrossRefGoogle Scholar
  45. 45.
    Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Drug Development Unit, The Institute of Cancer ResearchICR and Royal Marsden NHS Foundation TrustSurreyUK

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